NeuroEndocrine Tumors Diagnostic and therapeutic challenges: introduction Prof Eric Van Cutsem, MD, PhD Gastroenterology/Digestive Oncology Leuven, Belgium
Introduction to Neuroendocrine Tumours Neuroendocrine tumours (NET) are relatively rare; this is associated with limited knowledge on disease management The natural history of NET is poorly understood At least 40 different entities are described arising in different organs; different terminologies have also caused confusion
Diagnostic & therapeutic challenges in NET Heterogeneous group of tumors Wide variety of clinical presentations Late presentation Over 60% of NETs are advanced at the time of diagnosis The median survival for patients with advanced NET is 33 months Different terminology and classifications Histologic diagnosis may be difficult Variety of therapeutic options/approaches Limited phase III evidence for chemotherapy and PRRT
Neuroendocrine Tumors (NETs): A Diverse Group of Malignancies, a Clinical Challenge Neuroendocrine cells: migrated from the neural crest to the gut endoderm, from multipotent stem cells Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body NETs present with functional and nonfunctional symptoms and include a heterogeneous group of neoplasms 1,2 Multiple endocrine neoplasia (MEN)de, type 1 and type 2/medullary thyroid carcinoma Gastroenteropancrtic neuroendocrine tumors (GEP-NETs) Islet cell tumors Pheochromocytoma/paraganglioma Poorly differentiated/small cell/atypical lung carcinoid Small cell carcinoma of the lung Merkel cell carcinoma
Overview of Neuroendocrine Tumors (NETs) NETs are sometimes called carcinoid tumors Can be both symptomatic and asymptomatic May be undetected for years without obvious signs or symptoms NETs are generally characterized by their ability to produce peptides that lead to their syndromes NETs are generally classified as foregut, midgut, or hindgut depending on their embryonic origin 3 Foregut tumors develop in the respiratory tract, thymus, stomach, duodenum, and pancreas Midgut tumors develop in the small bowel, appendix, and ascending colon Hindgut tumors develop in the transverse colon, descending colon, or rectum Pancreatic NETs Insulinoma Glucagonoma VIPoma Pancreatic polypeptidoma Other NETS Foregut Thymus Esophagus Lung Stomach Duodenum Midgut Appendix Ileum Cecum Ascending colon Hindgut Distal large bowel Rectum
Incidence per 100,000 - NETs Incidence per 100,000 All malignant neoplasms Incidence of NETs Increasing 6.00 5.00 All malignant neoplasms 600 500 4.00 400 3.00 300 2.00 200 1.00 Neuroendocrine tumors 100 0.00 1973 1974 1975 1976 1977 1978 1979 1980 1981 1983 1982 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 0 Yao JC et al. J Clin Oncol. 2008;26:3063-3072.
Incidence rates per 100,000 US and European Incidence of NET 6.0 Men Women 4.0 2.0 0.0 Country: USA 1 (SEER) Sweden 2 Netherlands 2 Norway 3 Switzerland 2 Italy 2 (Vaud) (Tuscany) Study Period: 2000-2004 1983-1998 1989-1996 1993-2004 1974-1997 1985-1991 1 Yao J, et al. J Clin Oncol. 2008;26:3063-3072. 2 Taal BG, et al. Neuroendocrinology. 2004;80(suppl 1):3-7. 3 Hauso O, et al. Cancer. 2008;113:2655-2664.
Cases (thousands) NETs Are Second Most Prevalent Gastrointestinal Tumor 1200 1100 NET Prevalence in the US, 2004 103,312 cases (35/100,000) Median survival (1988 2004) Localized 203 months Regional 114 months Distant 39 months 100 0 Colon Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary 29-year limited duration prevalence analysis based on SEER. SEER: Surveillance, Epidemiology, and End Results. Yao JC et al. J Clin Oncol. 2008;26:3063-3072.
The GI Tract Is the Most Common Primary Location of NET (US SEER Data) Percent distribution (%) 17.2 Rectum Lung 13.4 Jejunum/ileum Other/ Unknown 15% 27% Digestive system 58% 6.4 Pancreas 6.0 Stomach 4.0 Colon 3.8 Duodenum 3.2 Cecum 3.0 Appendix 0.8 Liver Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.
The Pancreas Is the Most Common Primary Location of NET Breakdown (Middle East & Asia Pacific Region) Bile duct and gallbladder 3% Omentum/abdominal lining 1% Rectum 1% Ovary 1% Lung 1% Liver 4% Stomach 6% Hwang T, et al. Presented at: 8 th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C48.
Neuroendocrine Cells Are Peptide Hormone-Producing Cells that Share a Neural-Endocrine Phenotype Synaptophysin Small synaptic vesicles Chromogranin A Membrane protein of neurosecretory granules Peptide hormone In neurosecretory granule Secreted into the serum biomarkers Klöppel G. et al. International Collaboration on Neuroendocrine Tumours. Vienna, Austria. 2011. NET
Cells of Origin Stem cell Gastrointestinal neuroendocrine lineages arise from a common stem cell precursor in the base of the intestinal crypts or in the neck of the gastric glands Differentiate into diverse types of neuroendocrine cells under the influence of transcription factors Math1 and neurogenin 3 (NGN3) Non-secretory cell lineage Secretory lineages Math1+ NGN3+ Enterocytes Goblet cells Paneth cells Endocrine cell lineages Beta2 Pax4 Pax6 Endocrine cell types Gastrin GI P Secretin 5-HT CCK S P SST GLP-1, PYY/NT Image courtesy of IM Modlin.
Role of CgA IHC in the Diagnosis of NET Benefits: Can be detected in the secretory granules of most NET both symptomatic and asymptomatic Limitations: Many NET of the large bowel and some of the appendix primarily secrete CgB CgA may be negative in poorly differentiated NET CgA CgA Taupenot L, Harper KL, O Connor DT. N Engl J Med. 2003;348:1134-1149. Syn
Role of Synaptophysin IHC in the Diagnosis of NET Benefits: Expressed independently of secretory granules Useful in identifying poorly granulated and poorly differentiated NET that may not exhibit CgA staining Limitations: Expression is not limited to neuroendocrine cells Chetty R et al. Arch Pathol Lab Med 2008;132:1285-1289.
Immunohistochemical NE Markers Definition of hormonal production Glucagon
Neuroendocrine Tumours WHO Classification 2010 of the Digestive System Neuroendocrine tumour/ NET (Carcinoid) Neuroendocrine carcinoma / NEC
Neuroendocrine Tumours WHO Classification 2010 of the Digestive System Working principles Neuroendocrine defines the peptide hormone-producing tumours and share neural-endocrine markers The term Neuroendocrine neoplasm includes well- and poorly differentiated tumours Premise: All neuroendocrine neoplasms (NEN) have a malignant potential This premise has an influence on the incidence data Initially, NET that were regarded as benign were not considered in the incidence data (eg, SEERS data) NET now have to be included because they are known to have malignant potential Bosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.
Neuroendocrine Tumours (NET): A Stepwise Diagnostic Approach 1. NET vs nonnet morphology & NE markers 2. NET vs NEC structure + grade 3. Grade 1-2-3 mitoses & Ki67 4. TNM Stage I-II-III-IV size & invasion
Confusion Caused by the Term Carcinoid Oberndorfer coined the term karzinoide in 1907 1 This term implies that these tumours are benign; this is an unfortunate misnomer for the majority of NET NET have malignant potential and metastasize, generally to the liver Referring to any NET, the term carcinoid should only be used in reference to carcinoid syndrome Symptoms of carcinoid syndrome include flushing, abdominal cramps, and diarrhea 2 Most cases are associated with tumours of the intestines, which frequently metastasize to live 2 1 Klöppel G, et al. Endocr Pathol. 2007;18:141-144. 2 Bhattacharyya S, et al. Nat Rev Clin Oncol. 2009;6:429-433.
Carcinoid Syndrome Occurs in approximately 8% to 35% of patients with NETs and occurs mostly in cases of patients with hepatic metastases 1 Percentage of patients with symptoms of carcinoid syndrome 4 Consequence of vasoactive peptides such as serotonin, histamine, or tachykinins released into the circulation 2,3 Manifested by episodic flushing, wheezing, diarrhea, and, potentially, the eventual development of carcinoid heart disease 2,3 1. Rorstad O. J Surg Oncol. 2005; 89:151-60. 2. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Gastroenterology. 2005;128:1717-1751. 3. Vinik A, Moattari AR. Dig Dis Sci. 1989;34(3 Suppl):14S-27S. 4. Creutzfeldt W. World J Surg. 1996;20:126-131.
WHO Classifications of Neuroendocrine Neoplasms of the GEP System WHO 1980 WHO 2000 WHO 2010 I. Carcinoid Well-differentiated endocrine tumour (WDET) Well-differentiated endocrine carcinoma (WDEC) Neuroendocrine tumours Grade 1 Grade 2 II. Mucocarcinoid III. Mixed forms carcinoidadenocarcinoma IV. Pseudotumour lesions Poorly differentiated endocrine carinoma/small-cell carcinoma (PDEC) Mixed exocrine-endocrine carcinoma (MEEC) Tumour-like lesions (TLL) Neuroendocrine carcinoma Grade 3 Mixed adenoneuroendocrine carcinoma (MANEC) Hyperplastic and preneoplastic lesions Bosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.
Staging of NET According to Tumour-Node-Metastasis (TNM) The European Neuroendocrine Tumour Society (ENETS) and American Joint Committee on Cancer (AJCC) have developed TNM staging systems Staging systems are developed for the following tumour locations: Gastric, duodenum/ampulla/proximal jejunum, pancreas 1 Lower jejunum and ileum, appendix, and colon and rectum 2 1 Rindi G, et al. Virchows Arch. 2006;449:395-401; 2 Rindi G, et al. Virchows Arch. 2007;451:757-762.
ENETS/AJCC TNM Staging Systems ENET/AJCC Classification Criteria GI NET Stage includes tumour location, size, lymph node involvement/distant metastasis Stage I T1 N0 M0 Stage IIa T2 N0 M0 Stage IIb T3 N0 M0 Stage IIIa T4 N0 M0 Stage IIIb Any T N1 M0 Stage IV Any T Any N M1 ENETS = European Neuroendocrine Tumour Society AJCC = American Joint Committee on Cancer 1 Rindi G, et al. Virchows Arch. 2006;449:395-401. 2 Rindi G, et al. Virchows Arch. 2007;451:757-762. 3 American Joint Committee On Cancer. AJCC Cancer Staging System. 7 th ed.
Cumulative survival Correlation of Tumour Stage and Cumulative Survival (ENETS TNM Staging Proposal) 1.0 Stage I Stage II 0.8 0.6 0.4 Stage III Stage IV I vs II P =.227 I vs III P =.048 I vs IV P<.001 II vs III P =.171 II vs IV P<.001 III vs IV P =.004 0.2 0.0 0 50 100 150 200 250 Survival time (months) 202 cases: gastric (48), duodenal (23), pancreatic (131) Pape UF, et al. Cancer. 2008;113:256-265.
Grading of GEP-NET According to ENETS/WHO/AJCC Grade G1 G2 G3 Ki67 index (%)** 2 3 20 >20 MI (mitotic count)* <2 2-20 >20 *10 HPF (high power field) = 2 mm 2, at least 40 fields (at 40 magnification) evaluated in areas of highest mitotic density. ** MIB1 antibody; % of 2,000 tumour cells in areas of highest nuclear labeling. 1. Rindi G, et al. Virchows Archiv. 2006;449:395-401. 2. Rindi G, et al. Virchows Archiv. 2007;451:757-762.
Mitoses/10 HPF Metastatic GEP-NET: Correlation Between Mitotic Count and Ki-67 Index 100 90 80 70 60 50 40 30 20 10 0 0 R Sq Linear = 0.813 10 20 30 40 50 60 70 80 90 100 Ki-67 Strosberg J, et al. Human Pathology. 2009;40:1262-1268.
Cumulative survival Correlation of Tumour Grade and Cumulative Survival (ENETS Grading Proposal) 1.0 0.8 G1 G2 0.6 Grade 1 Mitotic count Ki-67 index (10 HPF) 2 (%) 3 0.4 0.2 G1 vs G2 G1 vs G3 G2 vs G3 P =.040 P.001 P.001 G1 2 2 G2 2-20 3-20 G3 20 20 0.0 G3 0 50 100 150 200 250 Time (months) 1 ENETS grading system. 2 10 HPF = 2 mm 2 at least 40 fields (40 magnification) evaluated in areas of highest mitotic density. 3 Percentage of 2,000 tumour cells in areas of highest nuclear labeling with MIB1 antibody. Pape UF, et al. Cancer. 2008;113:256-265.
Survival rates % Metastatic Well-Differentiated Neuroendocrine Neoplasms: Prognosis 1.0 0.9 No Risk Factors 0.8 0.7 0.6 1 Risk Factor Prognostic factors (MV analysis): Age >65 years 0.5 0.4 0.3 0.2 3 Risk Factors 2 Risk Factors Number of liver metastases (>10) Tumour progression (100% if Ki67 >10%) Primary not removed 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 Years after metastases MV = mean variance Durante C, et al. Endocr Rel Cancer. 2009;16:585-597.
Survival probability Correlation of Primary Tumour Site with Survival Known prognostic factors include: Location of primary tumour Extent of disease Tumour stage Degree of differentiation/ proliferative index (PI) 1.0 0.8 0.6 Distant Metastases Colon Lung Pancreas Rectum Small bowel Tumour grade Patient age 0.4 Performance status 0.2 0 12 24 36 48 60 72 84 96 108 120 Time (months) 65% of patients with advanced NET will not be alive in 5 years Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.
Biomarkers in NET CgA is the best available biomarker for diagnosis of NET Elevated CgA may correlate with tumour progression CgA is elevated 80% to 100% of the time NSE is also expressed in NET Not as commonly used as CgA Also elevated in pnet and poorly differentiated NEC 5-HIAA reflects serotonin levels Elevated serotonin levels over time lead to comorbidities such as cardiac disease Other biomarkers are available, however, few have achieved widespread acceptance SSTR CgA NSE 5-HIAA New biomarkers in NET are needed to provide better diagnostic and prognostic information VIP 5-HT Gastrin Insulin Glucagon CgA = Chromogranin A; 5-HIAA = 5-hydroxy-3-indoleacetic acid, 5-HT = serotonin, NSE = neuron-specific enolase, VIP = vasoactive intestinal peptide; SSTR = somatostatin receptor Vinik A, et al. Pancreas. 2009;38:876-889.
Cumulative survival Correlation of Baseline CgA Levels with Survival 1.0 0.8 Chromogranin A μg/l <100 n = 6 100-1000 n = 16 >1000 n = 16 0.6 0.4 0.2 P =.02 0.0 0 20 40 60 80 100 Survival time (months) Korse C, et al. Neuroendocrinology. 2009;89:296-301.
CgA and NSE: Prognostic Biomarkers Nonelevated CgA Elevated CgA Nonelevated NSE Elevated NSE Everolimus, n 121 84 155 48 Median PFS, mos 11.2 8.5 13.86 8.11 HR (95% CI)* 1.2 (0.82, 1.76) 2.03 (1.33, 3.09) P value.173 <.001 Placebo, n 97 103 138 56 Median PFS, mos 4.9 4.3 5.36 2.83 HR (95% CI)* 1.33 (0.98, 1.82) 2.01 (1.43, 2.84) P value.035 <.001 Elevated baseline CgA were associated with shorter PFS in patients who received everolimus or placebo, suggesting that these biomarkers are predictive for outcome Everolimus improved PFS vs placebo regardless of patients baseline CgA levels PFS = progression-free survival * Obtained from unstratified Cox model. Obtained from unstratified 1-sided log-rank test. Öberg K, et al. Presented at: 8 th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C81.
PFS (%) PFS (%) 100 CgA and NSE: Predictive Biomarkers* CgA Median PFS (months) Early response (n/n = 16/33) = 13.3 No early response (n/n = 26/38) = 7.5 100 NSE Median PFS (months) Early response (n/n = 17/28) = 8.6 No early response (n/n = 10/11) = 2.9 80 Censored observations 80 Censored observations 60 HR = 0.25 95% CI: 0.13-0.51 P =.00004 60 HR = 0.25 95% CI: 0.10-0.58 P =.00062 40 40 20 20 0 0 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Time since study start (months) Time since study start (months) Patients at Risk Resp. 33 29 26 19 12 5 3 2 0 28 23 16 9 6 3 1 0 0 Nonresp. 38 26 12 5 1 1 0 0 0 11 5 2 0 0 0 0 0 0 *Data from RADIANT-1 clinical trial. An early CgA or NSE response was defined as normalization or 30% decrease at week 4. Yao JC, et al. J Clin Oncol. 2010;28(1):69-76.
Pathology Report of NET Define location and tumour type Define differentiation grade (including Ki-67 proliferative index) Describe the presence of additional histologic features (multicentric disease, non-ischemic tumour necrosis, vascular or perineural invasion) Assess the TNM stage Define the resection margins Define the hormonal production, if any Upon request, assess prognostic or predictive factors useful for target therapy (e.g. somatostatin receptors, mtor pathway molecules, other target enzymes, ) See also: Klimstra D, et al. Am J Surg Pathol. 2010;34:300-313.
Systematic Approach to Diagnosing NETs History and physical exam Characteristic symptoms (dry flushing, cramps, nocturnal diarrhea) Present in 8% to 35% of metastastic NETs 1 Biochemical markers Chromogranin A (CgA) Urinary 5-hydroxyindoleacetic acid [(5-HIAA) (with presence of carcinoid syndrome] Synaptophysin on biopsies Other biomarkers, including glucagon, gastrin Histologic diagnosis!!! (expertise) Imaging Computerized tomography scan (CT) Endoscopic ultrasound (mainly pancreatic-net and NET in duodenum) Magnetic Resonance Imaging (MRI) Somatostatin-receptor scintigraphy (Octreoscan ) or DOTA-TOC FDG/PET
Nomenclature Summary Neuroendocrine tumours originate from a wide variety of different cell types that can secrete their own peptide hormone Site = Pancreas vs intestine Organ of origin should be determined Nomenclature could be simplified by using location of origin Classification = Give a name to the disease WHO classification is based on morphology and clinical pathological information (and is independent from presence and type of hormone secretion) Staging = Measure the extent of the disease TNM staging for ENETS and AJCC is same for GI NET but differ for pnet (ENETS has proved preliminary clinical effectiveness while AJCC needs confirmation) Grading = Measure the pace of NET growth Mitosis count or Ki67 with cut-off at 5% and 20% discern prognosis between diseases
Classification of NET Functional versus non-functional Classification by site of origin nearly identical characteristics on routine histologic evaluation, but different responses to therapeutic agents Classification by tumor stage: TNM AJCC ENETS Histologic classification well differentiated - poorly differentiated tumors with a high grade (grade 3), a mitotic count >20 per10 high powered fields, or a Ki-67 proliferation index of >20% represent highly aggressive malignancies Molecular Classification MEN 1 & 2, Tuberosis Sclerosis, Von Hippel Lindau disease
Collaboration for optimal patient management Multidisciplinary patient management Clinical research team patient Expertise/ network Basic research team ENETS Centers of Excellence University hospitals Leuven